Despite nearly 50 years of clinical experience, the long-term safety of living kidney donation is not confidently known. Prior to donation, living kidney donors undergo careful medical screening. Candidate donors with kidney or cardiovascular disease or risk factors (such as diabetes or hypertension), and other serious medical conditions such as cancer are excluded. Some previous studies attempted to estimate the risk of living donation by comparing the outcomes of living kidney donors to unscreened general population cohorts. However, these unscreened cohorts do not allow for meaningful comparison, as they inevitably included individuals with conditions that would preclude donation. In addition, most previous investigations of living donor outcomes have examined only mortality or the prevalence of end-stage renal disease (ESRD). In contrast, our proposed study will use two existing data sources to compare long-term outcomes of a well-described cohort of living kidney donors matched at the age of donation to similarly-characterized and screened controls. We will determine whether death, ESRD, chronic kidney disease, cardiovascular disease, hypertension, and/or anemia become more common following living kidney donation than in these matched non-donors who would otherwise have been healthy enough to donate. Living kidney donor data are derived from the Renal and Lung Living Donors Evaluation (RELIVE) database, containing detailed information on 8,951 living kidney donors who donated at one of three US transplant centers between 1963 and 2007. The RELIVE data have been enriched with linkages to data from the National Death Index (NDI), Centers for Medicare & Medicaid Services (CMS), Social Security Death Master File (SSDMF), and Scientific Registry of Transplant Recipients/Organ Procurement and Transplantation Network (SRTR/OPTN) for additional ascertainment of death and ESRD. In addition, a subset of surviving RELIVE donors (N= 2,857) participated in follow-up surveys and physical assessments between 2010 and 2012 to detect ESRD and kidney-related morbidities such as chronic kidney disease, cardiovascular disease, hypertension, and anemia. Control data will be assembled from six cross-sectional National Health and Nutrition Examination Survey (NHANES) cohorts covering most years between 1971 and 2004, with newly available longitudinal follow-up of mortality and health status from NDI and CMS linkages. Data are available on myriad health conditions existing at the time of NHANES participation, allowing a selection algorithm for controls approximating the screening process for living kidney donation. The year ranges for RELIVE donations and NHANES participants are largely overlapping, allowing similar follow-up for age- and birth-cohort matched pairs. Because this study will use an appropriate control group, include the longest follow-up, and assess multiple outcomes, it will provide the best long-term assessment of live kidney donation to date. PUBLIC HEALTH RELEVANCE: The Renal and Lung Living Donors Evaluation Study (RELIVE) project studied medical and quality of life outcomes for living kidney donors who donated between 1963 and 2007 at three US transplant centers. In order to help doctors, previous donors, and people who are considering living kidney donation understand how donating a kidney affects life expectancy, future kidney health, and overall health, we plan to compare the nearly 9,000 living donors from the RELIVE study with people who participated in another study that looked at overall health in the United States (NHANES). The matched controls from NHANES will be chosen to be similar to and just as healthy as the RELIVE kidney donors in every way, except for not having donated a kidney. Since the only difference between the donors and the controls will be the kidney donation, we will be able to draw more accurate conclusions about kidney donor outcomes that are connected to the donation itself.